Abstract
Pancreatic beta cell failure plays a central role in the development and progression of type 2 diabetes (T2D). The endoplasmic reticulum (ER) is a central organelle for the massive production and processing of proinsulin. The disruption of ER homeostasis, by many genetic and environmental diabetes-causing factors, induces ER stress and causes beta cell death in T2D. Among the key components to maintain beta cell ER homeostasis, the role of ER export in insulin biogenesis is the least understood. Our recent results demonstrated that ER exit of proinsulin requires COPII (coat protein complex II) coated vesicles and defective COPII dependent ER export strongly induces ER stress and beta cell death. In spite of the essential role of beta cell ER in insulin biogenesis and diabetes, its protein composition has not been systemically analyzed previously. To fill this knowledge gap, we conducted a comprehensive proteomic analysis of purified beta cell ER and identified a total of 1467 proteins. These proteins included known and novel players in insulin biogenesis and ER homeostasis, some being beta cell specific and some present in the risk genetic loci of T2D. Our study has defined the molecular environment in beta cell ER for proinsulin synthesis, folding, export and degradation. Our ongoing studies use innovative proteomics, biochemical and quantitative imaging approaches, in beta cells, diabetic mouse and human T2D islets, to determine the molecular mechanisms by which diabetes-causing factors disrupt beta cell ER homeostasis and COPII dependent ER export. This study is expected to provide novel insights and therapeutic strategies, by targeting the COPII dependent pathway and related ER folding environment, to improve proinsulin processing and beta cell ER export, alleviate chronic ER stress and beta cell death in diabetes.